The protein-tyrosine kinases (PTKs) are a large family of enzymes that regulate important biological processes requiring intercellular communication, such as cell differentiation and growth. It is not surprising therefore that disrupted PTKs can lead to abnormal development, impaired immune system function, and carcinogenesis. To further investigate the potential functions of PTKs in multicellular organisms and the molecular components of their signal transduction pathways, an analysis of PTKs in the model organism C. elegans was previously initiated. The C. elegans genes ktn-15 and kin-16 encode novel transmembrane PTKs expressed in the post-embryonic hypodermis (epidermis) as it grows by cell fusion. To elucidate the organismal role of these PTKs further, the phenotypic effects of kin-15 and kin-16 gene disruptions will be examined at the cellular level. To start, Tc1-mediated deletions removing both PTK genes will be isolated by a PCR/sib-selection scheme to examine the double mutant phenotype. Subsequently, the single mutant phenotype will be investigated using complementing transgenic arrays in the double mutant background. The phenotypic analysis will include an examination of hypodermal cell fusions to investigate athe potential role of these PTKs in the development and function of the hypodermis. Binding of a signal molecule to the typically large extracellular domain of transmembrane PTKs leads to their activation. However, Kin-15 and kin-16 have unusually short extracellular domains, apparently precluding a similar regulatory mechanism. To distinguish between several alternative possibilities for Kin-15 /Kin-16 regulation, in the proposed research the functional protein domains will be delineated based on evolutionary conservation and site-directed mutagenesis studies.